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JNNP Online First, published on February 19, 2014 as 10.1136/jnnp-2013-307207

Multiple sclerosis

RESEARCH PAPER

Autologous haematopoietic stem cell

transplantation for aggressive multiple sclerosis:
the Swedish experience
Joachim Burman,1,2 Ellen Iacobaeus,3 Anders Svenningsson,4 Jan Lycke,5
Martin Gunnarsson,6,7 Petra Nilsson,8 Magnus Vrethem,9,10 Sten Fredrikson,11
Claes Martin,12 Anna Sandstedt,13 Bertil Uggla,7,14 Stig Lenhoff,15
Jan-Erik Johansson,16 Cecilia Isaksson,17 Hans Hgglund,18 Kristina Carlson,18
Jan Fagius1,2
Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
jnnp-2013-307207).
For numbered afliations see
end of article.
Correspondence to
Dr Joachim Burman,
Department of Neurosciences,
Uppsala University Hospital,
Uppsala SE-751 85, Sweden;
joachim.burman@neuro.uu.se
Received 7 November 2013
Revised 27 January 2014
Accepted 29 January 2014

ABSTRACT
Background Autologous haematopoietic stem cell
transplantation (HSCT) is a viable option for treatment of
aggressive multiple sclerosis (MS). No randomised
controlled trial has been performed, and thus,
experiences from systematic and sustained follow-up of
treated patients constitute important information about
safety and efcacy. In this observational study, we
describe the characteristics and outcome of the Swedish
patients treated with HSCT for MS.
Methods Neurologists from the major hospitals in
Sweden lled out a follow-up form with prospectively
collected data. Fifty-two patients were identied in total;
48 were included in the study and evaluated for safety
and side effects; 41 patients had at least 1 year of
follow-up and were further analysed for clinical and
radiological outcome. In this cohort, 34 patients (83%)
had relapsing-remitting MS, and mean follow-up time
was 47 months.
Results At 5 years, relapse-free survival was 87%; MRI
event-free survival 85%; expanded disability status scale
(EDSS) score progression-free survival 77%; and diseasefree survival (no relapses, no new MRI lesions and no
EDSS progression) 68%. Presence of gadoliniumenhancing lesions prior to HSCT was associated with a
favourable outcome (disease-free survival 79% vs 46%,
p=0.028). There was no mortality. The most common
long-term side effects were herpes zoster reactivation
(15%) and thyroid disease (8.4%).
Conclusions HSCT is a very effective treatment of
inammatory active MS and can be performed with a
high degree of safety at experienced centres.

INTRODUCTION

To cite: Burman J,
Iacobaeus E,
Svenningsson A, et al.
J Neurol Neurosurg
Psychiatry Published Online
First: [ please include Day
Month Year] doi:10.1136/
jnnp-2013-307207

Autologous haematopoietic stem cell transplantation

(HSCT) has been used as treatment for multiple
sclerosis (MS) since 1995.1 Initially, this therapy was
reserved for patients with treatment-resistant progressive forms of MS, but despite initial optimism, it
soon became evident that the procedure was not
able to stop deterioration in patients with progressive disease.2 However, in the following years it
became clear that HSCT could be a very effective
treatment for relapsing-remitting MS (RRMS), and
in particular highly aggressive RRMS.3 4 It seems

Burman
J, et al. J Neurol
Neurosurg
Psychiatry
doi:10.1136/jnnp-2013-307207
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Article
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2014. Produced

that long-term remission, and maybe even cure, can

be achieved.58
The goal of this therapy is to achieve long-term
remission through short-lasting ablation of the
immune system. The mode of action is not yet fully
understood, and several mechanisms probably contribute to the effect. We know that HSCT causes a
profound renewal of the immune system and not
just long-lasting immune suppression.9 At least part
of the effect is likely related to removal of autoreactive cells, but some of these cells probably
escape the treatment and remain after HSCT.10
Such autoreactive cells must be kept in control to
maintain remission, which could be due to restoration of tolerance to self-antigens.11
HSCT was introduced in Sweden in 2004 at the
Uppsala University Hospital as rescue therapy for
aggressive MS. Following the rst and encouraging
experiences,3 neurologists from other major
Swedish hospitals consulted with Uppsala
University Hospital when considering this treatment. Thereby, clinical criteria for the use of HSCT
were proposed as follows: diagnosis of RRMS;
aggressive disease with high relapse frequency;
short duration of aggressive disease with documented potential for recovery during the previous
6 months; and failure of conventional treatment.
Moreover, an informal but systematic common
routine for prospective clinical and radiological
follow-up was agreed upon.
So far, no randomised controlled trial of HSCT
has been performed. A few case series, consisting
mainly of patients with primary or secondary progressive disease, have been published.1 2 57 12
Systematic follow-up data from patients with
RRMS are still scarce;3 4 such data are a valuable
addition to our knowledge of safety and efcacy of
this treatment. The purpose of this study was to
describe the characteristics and outcome of the
Swedish patients.

METHODS
Subjects
Neurologists from all the major hospitals in
Sweden were contacted in order to identify MS
patients that had been treated with HSCT for MS.
Physicians were asked to obtain consent from the

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Multiple sclerosis
patients and to ll out a follow-up form with prospectively collected data obtained at each neurologistpatient encounter. This
form included demographical data, prior treatment, type of
HSCT, expanded disability status scale score (EDSS)13 before
and after the procedure, MRI and cerebrospinal uid (CSF)
data, side effects and pregnancies.
In total, 52 patients were identied. After scrutiny, four of
these had been treated for a concurrent autoimmune disease
and/or had an uncertain diagnosis of MS. The remaining 48
patients were included in the study. The rst patient was treated
in May 2004; the last included patient was treated in April
2013. Patients were distributed in the following way: Uppsala,
n=19; Stockholm, n=14; Gothenburg, n=4, Ume, n=4;
rebro, n=3; Linkping, n=2; Lund, n=2.
Twenty-two patients were men and 26 women. Forty patients
had RRMS; ve had secondary progressive MS (SPMS); two
had primary progressive MS; and one had progressive-relapsing
MS. About half the patients did not meet one or more of the
above-mentioned clinical criteria for HSCT as rescue therapy for
aggressive RRMS; the major exception was the eight patients
with progressive MS. These were transitional cases of SPMS or
compassionate care for patients considered by their treating
neurologist to have exhausted all other forms of therapy. The
mean age at HSCT was 31 years (range 952). Mean disease
duration prior to HSCT was 75 months (range 4300); for
RRMS patients mean duration was 66 months (range 4192).
The mean annualised relapse rate (ARR) in the year prior to
HSCT was 4.1 (range 012); ARR for RRMS patients only was
4.8 (range 012). The median patient had tried two treatments
prior to HSCT (range 04). Previous treatments were: interferon (n=36), natalizumab (n=21), glatiramer acetate (n=18),
mitoxantrone (n=15), intravenous immunoglobulins (n=4), ngolimod (n=2) and rituximab (n=2). Four patients had no previous treatment.

Procedure
Peripheral haematopoietic stem cells were mobilised with
cyclophosphamide and lgrastim according to local routine. In
typical cases, a single dose of 2 g/m2 cyclophosphamide and lgrastim 510 mg/kg/day for 67 days were administrated. No ex
vivo graft manipulation was performed. In most cases, patients
were admitted for conditioning about 3 weeks after mobilisation. Two different protocols for the conditioning were used. A
majority of patients (n=41) were treated with the BEAM/ATG
protocol
(BCNU
300 mg/m2;
etoposide
800 mg/m2;
2
cytosine-arabinoside 800 mg/m ; melphalan 140 mg/m2; ATG
7.510 mg/kg). Seven patients (RRMS, n=4; SPMS, n=2;
primary progressive MS, n=1) were treated with a cyclophosphamide/ATG protocol (cyclophosphamide 200 mg/kg; ATG
10 mg/kg). Prophylaxis against fungal, viral and bacterial infection was administrated during neutropenia. Prophylaxis against
varicella virus and Pneumocystis carinii continued for an additional 3 months. Patients were hospitalised for a mean of
24 days (range 1038) during HSCT.

inammatory activity. Patients were not treated with any diseasemodulating drugs post-HSCT if they were stable.

Statistical analysis
Statistical analyses were done with GraphPad Prism V.5.0
(GraphPad Software, La Jolla, California, USA). The paired t
test was used to establish statistical signicance between different time points. A two-tailed p value of <0.05 was considered
signicant. Survival at different time points was estimated with
KaplanMeier survival curves and analysis of the statistical signicance of the difference between two survival curves was
done with the log-rank test.

RESULTS
Seven patients had less than a year follow-up time. These were
excluded from further analysis with exception for description of
toxicity and side effects. The remaining 41 patients were analysed further (RRMS, n=34; progressive forms of MS, n=7).
Their mean follow-up time was 47.4 months (range 12108
months), and in total, 162 patient-years of follow-up time were
analysed.

Relapses
Four patients experienced a relapse post-HSCT (6, 11, 14 and
31 months after HSCT). One of these patients went on to have
another relapse, nearly 5 years after HSCT. This equates to a
post-HSCT ARR of 0.03 or one relapse for every 33rd year of
follow-up. All relapses were conrmed by demonstration of a
new gadolinium-enhancing lesion on an acute MRI.
One of these relapses was treated with high-dose corticosteroids, the remaining were not treated. As a direct consequence of
the relapses, disease modifying drug treatment with glatiramer
acetate was started in three patients. In one of those, treatment
was subsequently changed to intravenous immunoglobulin due
to pregnancy. No other disease modifying drug treatment was
used post-HSCT in this cohort.

EDSS
Progression of EDSS was dened as deterioration by at least 0.5
points sustained at subsequent follow-up visits. Eight patients
progressed with this denition. The evolution of EDSS is summarised in table 1. The median EDSS when the decision for
HSCT was made was 6 (range 18.5). The median EDSS at the
latest follow-up was 4 (range 08). The median change in EDSS
was 0.75 (range 7 through 1.5); if patients with progressive
disease are excluded from the analysis, the median change was
1.5 (range 7 through 1.5). The median of the lowest EDSS
in the year preceding HSCT was 3 (range 07.5; for patients
with a disease duration <1 year, this score was by denition

Table 1

Follow-up
Prospective follow-up included EDSS scoring at 3 and 6 months
after HSCT and then yearly; MRI investigation at baseline and
then at 6 months after HSCT, followed by yearly investigations
up to 3 years, thereafter every other year. Sixteen patients
underwent repeated lumbar puncture (optional) before and
after HSCT. Patients were asked to contact their treating physicians if they experienced new symptoms. If a relapse was suspected, an MRI investigation was made to conrm
2

Evolution of EDSS

Pre-HSCT

RRMS
PRMS

At HSCT

Post-HSCT

Lowest
EDSS

Highest
EDSS

EDSS

EDSS at
1 year

EDSS at
2 years

2.5 (06.5)
6.5 (57.5)

6 (3.59)
6.5 (68)

5.5 (1.58.5)
6.5 (68)

3.25 (07)
6.5 (68)

3 (07)
6.5 (67.5)

EDSS values are described as median (range).

The lowest and highest pre-HSCT EDSS are the lowest and highest EDSS scores
recorded in the year preceding HSCT.
EDSS, expanded disability status scale; HSCT, haematopoietic stem cell
transplantation; PRMS, progressive forms of multiple sclerosis; RRMS,
relapsing-remitting multiple sclerosis.

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Multiple sclerosis
always 0). The median of the highest EDSS was 6 (range 3.59).
The greater part of the EDSS improvement occurred in the rst
year after HSCT. Improvement occurring more than 2 years
after HSCT was seen in only one patient (EDSS at 2 years
2.0; 3 years 1.5; and 6 years 1.0). The evolution of EDSS in
patients with RRMS and progressive forms of MS are summarised in table 1.

MRI
At baseline, 16 patients had no gadolinium-enhancing (Gd+)
lesions, 25 patients had at least one Gd+ lesion; 13 patients had
more than 10 Gd+ lesions; and 6 patients more than 30 Gd+
lesions. Five patients had MRI activity after HSCT with new T2
lesions and/or new Gd+ lesions; four of these also had a clinical
relapse (see above). In total, ve new Gd+ lesions and eight
new T2 lesions were detected, equating to one new T2 lesion
for every 20th year of follow-up.

Analysis of the CSF

All patients who were examined prior to HSCT (n=26) had oligoclonal bands in the CSF. The mean value of the IgG index
was 0.81 (0.24). Sixteen patients were examined after HSCT,
11 (69%) retained oligoclonal bands in the CSF. The mean IgG
index post-HSCT was signicantly lower in comparison to the
pre-HSCT value in those patients (0.850.25 vs 0.630.12,
p=0.0007).

Survival and prognostic factors

At 5 years, relapse-free survival was 87%; MRI event-free survival was 85%; EDSS score progression-free survival was 77%;
and disease-free survival (ie, no relapses, no new MRI lesions
and no EDSS progression) was 68% (gure 1). Presence of Gd+
lesions prior to HSCT was associated with a favourable outcome
(disease-free survival 79% vs 46%, p=0.028). Other factors,
such as disease duration, relapsing-remitting disease course and
EDSS were analysed, but no statistically signicant differences
could be demonstrated (gure 2). No difference arose between
patients treated with the BEAM/ATG protocol (n=35) vis-a-vis
patients treated with the cyclophosphamide/ATG protocol
(n=6) (disease-free survival at 5 years 70% vs 56%, p=0.76). A
full account of the differences in outcome between patients
treated with the BEAM/ATG vis-a-vis cyclophosphamide/ATG
protocol is available in the supplementary section (see online
supplementary table S1).

Safety and side effects

Overall, no mortality was recorded and no patient required
treatment in the intensive care unit. Almost all patients experienced acute toxicity during hospitalisation, with the well-known
and expected side effects of alopecia, anaemia, thrombocytopenia and leukopoenia. Additionally, somewhat less than half
the patients experienced fever with bacteraemia, while neutropenic fever with negative blood cultures was seen in about a
third (table 2). One patient was diagnosed with invasive fungal
infection and was successfully treated with uconazole. After
discharge from the ward, very few adverse events were
recorded, the most common being reactivation of herpes viruses
(table 2). No clinically relevant infection with reactivated cytomegalovirus or EpsteinBarr virus was diagnosed.
Late side effects consisted mainly of herpes zoster reactivation
and thyroid disease. Eight patients (17%) experienced herpes
zoster reactivation (4 during the rst year; 3 during the second
year; and 1 during the third year after HSCT) and four patients
(8.3%) developed thyroid disease (two with hypothyreosis; one

with hyperthyreosis; and one with both in succession).

Additionally, one patient developed Crohns disease; one patient
developed alopecia areata; and one patient contracted epilepsy.
No patient developed malignancy during the follow-up period.

Pregnancy
During the follow-up period, a total of eight pregnancies arose
in four women. Five healthy infants were born (in one instance
a pair of twins); two spontaneous abortions and one ectopic
pregnancy occurred; one legal abortion was performed.
Additionally, one man became father to a healthy child conceived by in vitro fertilisation with cryopreserved semen, and
one woman became mother to a healthy infant after in vitro fertilisation with cryopreserved eggs after an otherwise normal
pregnancy.

DISCUSSION
In this nation-wide survey, we have demonstrated that HSCT
with a low or intermediate intensity protocol is a highly effective treatment of MS, and a majority of patients display no signs
of disease activity at follow-up. Patients with inammatory
disease activity prior to treatment are more likely to respond to
the procedure. Additionally, we have demonstrated that HSCT
can be performed safely at experienced centres, with a low risk
for serious complications.
Safety of the procedure has been a major concern. In 2006, it
was reported that treatment-related mortality (TRM) in Europe
was 5.3%.12 In the same report it was also noted that treatment
with busulphan inferred a greater risk of death. In a later report
describing the outcome of 74 Italian patients treated with
BEAM, TRM was 2.7%,6 and in a smaller Czech study of 25
patients treated with BEAM, there were no fatalities.5 Recently,
no TRM was reported in a single-centre study encompassing 95
Russian patients treated with a reduced-intensity conditioning
regimen based on BEAM.14 In our study there was no TRM.
This might be related to the Swedish practice, where HSCT is
only performed at university hospitals with a wealth of experience from treatment of haematological diseases. Another
important factor may be the low prevalence of multiresistant
bacteria in Swedish hospitals.
The treatment response was most notable in the group of
patients with on-going inammatory activity at baseline.
Post-HSCT, 79% of these patients had no new MRI lesions, no
relapses and no EDSS progression. When present, new disease
activity was predominantly seen during the rst 2 years after
HSCT. No patient who had been free from disease activity
during the rst 3 years following HSCT went on to have a clinical relapse or new MRI lesions. Similar evolution of
progression-free survival in RRMS patients have been described5
with few patients progressing beyond the time frame of
3 years.6 From a prognostic perspective, our data suggest that
freedom from disease during the rst 3 years after HSCT infers
an excellent prognosis.
The effect on prevention of formation of new T2 lesions was
most remarkable, with a total of eight new T2 lesions detected
after HSCT in the entire cohort. This is in stark contrast to the
disease course prior to HSCT, when a majority of patients were
inammatory active, and the disease course in many cases could
be described as malignant. This is also quite different from the
natural history as described in the clinical trials of drugs, such as
interferon , when patients in the placebo arm had an increase
of about six T2 lesions per year.15
The most used outcome measure in reports of the effects of
HSCT has been progression-free survival, which was 77% at

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Multiple sclerosis

Figure 1 KaplanMeier survival curves of relapse-free survival, MRI event-free survival, progression-free survival and disease-free survival.
Relapse-free survival, MRI event-free survival, progression-free survival and disease-free survival (no relapses, no new MRI lesions and no EDSS
progression) after haematopoietic stem cell transplantation for all patients with follow-up time at least 1 year (n=41). EDSS, expanded disability
status scale.

5 years. Previously, it has been reported in the range of

32100% at 35 years,46 14 16 and 25% at 15 years after
HSCT.7 The wide range of this measure is likely due to underlying differences in the treated cohorts (e.g, early
inammatory-active RRMS vs longstanding SPMS). Factors that

have been associated with a better outcome of HSCT are presence of Gd+ lesions at baseline,6 7 short disease duration5 14
and diagnosis of RRMS.5 In this study, we chose to use diseasefree survival at 5 years as main outcome measure (i.e, freedom
from all measurable forms of disease). We found a disease-free

Figure 2 Prognostic factors to the outcome of HSCT. Gd+, presence of gadolinium-enhancing lesion(s); Gd-, absence of gadolinium enhancing
lesions; RRMS, relapsing-remitting multiple sclerosis; EDSS, expanded disability status scale; HSCT, haematopoietic stem cell transplantation.
(A) Presence of gadolinium-enhancing lesions was a prognostic factor for higher disease-free survival (no relapses, no new MRI lesions and no EDSS
progression) at 5 years (79% vs 46%, p=0.028). (B-D) Disease duration, disease course and EDSS score could not be conrmed as statistically
signicant prognostic factors for disease-free survival.
4

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Multiple sclerosis
Table 2 Events related to acute toxicity

Bacteraemia
-haemolytic streptococci
Other streptococci
Coagulase-negative staphylococci
Neutropenic fever
Typhlitis
Mucositis
Clostridium difficile infection
ATG reaction (serum sickness)
Herpes simplex reactivation
Invasive candida albicans infection
Deep vein thrombosis
Pyelonephritis
Norovirus infection
Varicella zoster reactivation

During
hospitalisation

After
discharge

Per cent

Per cent

22
5
6
4
17
5
4
2
2

46
23
27
18
35
10
8.3
4.2
4.2

2.1

4.2

2.1
1
1
1
1

2.1
2.1
2.1
2.1

The table lists events related to acute toxicity (side affects appearing within 100 days
after haematopoietic stem cell transplantation). In the table, the three most common
bacteria present in blood cultures are listed. The percentages of these are proportions
of bacteraemic patients.

survival of 66% at 5 years, similar to the 62% at 5 years that

was reported previously in a smaller study.4
Presence of Gd+ lesions at baseline was favourable for the
outcome of the procedure. There are at least three different possible explanations to this phenomenon. First, patients with Gd+
lesions are more likely to have an inammatory disease
(as opposed to a degenerative disease), which would be responsive to HSCT. Second, a more permissible blood-brain barrier
could improve penetration of drugs into the central nervous
system. Last, rapidly proliferating autoreactive cells are probably
more susceptible to the procedure. If this is true, there may exist
a window of opportunity for treatment when the patient is
inammatory active. No other prognostic factor could be determined with statistical signicance.
It has been claimed that HSCT can reverse functional decits.
The median improvement of EDSS between the time point
when the decision of HSCT was made and the latest follow-up
was 0.75, and when patients with progressive forms of MS were
excluded from the analysis the improvement was 1.5. This is
slightly better than in the Italian study6 where only 31% of
RRMS patients improved >1 point in EDSS and on par with
the results from Burt et al.4 Some patients with very high EDSS
levels improved markedly; in the extreme, improvement from
the nadir of the disease with EDSS of 9.0, to 1.0 at the latest
follow-up. In all likelihood, the lions share of this improvement
is due to remyelination and resolution of conduction block. In
order to assess to which extent patients could improve from
more longstanding functional decits, likely of axonal origin,
we also included an analysis of the lowest recorded EDSS in the
year preceding HSCT. The average patient did not improve
from this time point indicating that the degree of functional
recovery from decits present for more than 1 year is low.
However, in nine cases (22%) such improvement was seen,
which implies regenerative mechanisms, or could be an effect of
neural reorganisation. During follow-up, EDSS scores
approached the lowest recorded EDSS value, indicating that
functional recovery is possible for almost all decits acquired in

the year preceding HSCT. The major part of the EDSS improvement took place during the rst year after HSCT, with some
additional improvement taking place during the second year,
and virtually none after that. This suggests that when inammatory activity has ceased, it takes about 2 years for the healing
process to reach its end, similar to what can be seen in a noninammatory condition such as stroke.17
The retrospective analysis of data and the uncontrolled nature
of this study is an obvious weakness. However, since these
patients had an unusually aggressive disease and received an offlabel treatment, they have been carefully monitored in a systematic and prospective way. Some reporter bias regarding EDSS
and/or formation of new T2 lesions may still have existed. On
the other hand, the near-abolition of inammatory MS activity
is convincing: a reduction of annualised relapse ratio from 4.1
to 0.03 and a frequency of new T2 lesions of 0.05 per year indicate a marked treatment effect, which is well within a large
margin of error. Additionally, the results from this study are in
line with other reports.
Taken together, an emerging corpus of evidence supports
HSCT as a very effective treatment of inammatory active MS,
and that the procedure can be performed with a high degree of
safety. Available data suggest that HSCT is superior to any other
disease modifying therapy in terms of effect; further, that
HSCT is on par with other advanced forms of immunotherapy,
such as alemtuzumab, in terms of safety.18 However, it is too
early to recommend a more widespread use of HSCT, before
more data from randomised controlled trials are available.
Currently, there is at least one phase III trial addressing this
issue (ClinicalTrials no. NCT00273364).
Author afliations
1
Department of Neuroscience, Uppsala University, Uppsala, Sweden
2
Department of Neurology, Uppsala University Hospital, Uppsala, Sweden
3
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute
Solna, Center for Molecular Medicine, Stockholm, Sweden
4
Department of Pharmacology and Clinical Neuroscience, Ume University and
University Hospital of Northern Sweden, Ume, Sweden
5
Department of Neurology, Institute of Neuroscience and Physiology, Sahlgrenska
University Hospital, Gothenburg, Sweden
6
Department of Neurology, rebro University Hospital, rebro, Sweden
7
School of Health and Medical Sciences, rebro University, rebro, Sweden
8
Department of Neurology, Skne University Hospital Lund, Lund, Sweden
9
Neurology and Clinical Neurophysiology, Faculty of Health Sciences, Department of
Clinical and Experimental Medicine, Linkping University, Linkping, Sweden
10
Department of Neurology and Neurophysiology, County Council of stergtland,
Linkping, Sweden
11
Department of Clinical Neuroscience, Karolinska Institute Huddinge, Stockholm,
Sweden
12
Neurology Unit, Division of Internal Medicine, Danderyd Hospital, Karolinska
Institute, Stockholm, Sweden
13
Department of Hematology, Linkping University Hospital, Linkping, Sweden
14
Division of Hematology, Department of Medicine, rebro University Hospital,
rebro, Sweden
15
Department of Hematology and Coagulation, Skne University Hospital, Lund,
Sweden
16
Department of Hematology and Coagulation, Sahlgrenska University Hospital,
Gothenburg, Sweden
17
Department of Radiosciences, Ume University, Ume, Sweden
18
Division of Hematology, Department of Medical Science, Uppsala University
Hospital, Uppsala, Sweden
Contributors ASa, BU, SL, J-EJ, CI, HH and KC performed the transplants and
provided data on acute toxicity. JF initiated the survey and the follow-up routine. JF
and JB worked out the data form. JF, EI, ASv, JL, MG, PN, MV, SF and CM
performed follow-up and lled out the forms. JB made the data analysis and wrote
the report. All authors critically read and revised the manuscript.
Funding This work was supported by the Swedish association of persons with
neurological disabilities, the MH Lndell foundation and Uppsala University
Hospital.

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Multiple sclerosis
Competing interests JB has received travel support and/or lecture honoraria from
Almirall, Biogenidec, Genzyme/Sanoaventis, Hospira and Merckserono; has received
an unconditional research grant from Merckserono. ASV has received travel support
and/or lecture honoraria from Biogenidec, Merckserono, Genzyme/Sanoaventis,
Novartis and Baxter; has received unconditional research grants from
Bayerscheringpharma and Biogenidec. JL has received travel support and/or lecture
honoraria from Bayerscheringpharma, Biogenidec, Novartis, Teva and Sanoaventis;
has served on scientic advisory boards for Almirall, Teva, Biogenidec, Novartis and
Genzyme/Sanoaventis; serves on the editorial board of the Acta Neurologica
Scandinavica; has received unconditional research grants from Biogenidec and
Novartis. MG has received travel support and/or lecture honoraria from Biogenidec,
Merckserono, Sanoaventis, Bayerscheringpharma; has served on scientic or
educational advisory boards for Merckserono, Bayerscheringpharma, and Teva; has
received unconditional research grants from Biogenidec. PN has been a member of
advisory boards and received honoraria for lectures from Biogen Idec, Merck Serono,
Sano Aventis, Novartis, Genzyme and received unrestricted grants from Biogen Idec.
MV has received an unrestricted grant for research from Biogen Idec And Novartis
and speaker Honoraria from Biogen Idec and Merck Serono; is a member of the
advisory board for Novartis. SF has received Honoraria for lectures, consultancy and
educational activities from Allergan, Bayer, Biogenidec, Genzyme, Merckserono,
Novartis, Sano and Teva. CM has participated in advisory board meetings for
Biogen Idec, Genzyme, Novartis and Teva. JF has received travel support and/or
lecture honoraria from Biogenidec, Genzyme/Sanoaventis and Merckserono; has
received an unconditional research grant from Biogenidec.
Ethics approval The study was approved by the local ethics committee of Uppsala
University (DNr 012/080). All subjects provided written informed consent.

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Provenance and peer review Not commissioned; externally peer reviewed.

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REFERENCES
1

Fassas A, Anagnostopoulos A, Kazis A, et al. Peripheral blood stem cell

transplantation in the treatment of progressive multiple sclerosis: rst results of a
pilot study. Bone Marrow Transplant 1997;20:6318.
Burt RK, Cohen BA, Russell E, et al. Hematopoietic stem cell transplantation for
progressive multiple sclerosis: failure of a total body irradiation-based conditioning
regimen to prevent disease progression in patients with high disability scores. Blood
2003;102:23738.
Fagius J, Lundgren J, berg G. Early highly aggressive MS successfully treated by
hematopoietic stem cell transplantation. Mult Scler 2008;15:22937.

15

16
17
18

Burt R, Loh Y, Cohen B, et al. Autologous non-myeloablative haemopoietic stem

cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study.
Lancet Neurol 2009;8:24453.
Krasulova E, Trneny M, Kozak T, et al. High-dose immunoablation with autologous
haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single
centre 10-year experience. Mult Scler 2010;16:68593.
Mancardi G, Sormani M, Di Gioia M, et al. Autologous haematopoietic stem cell
transplantation with an intermediate intensity conditioning regimen in multiple
sclerosis: the Italian multi-centre experience. Mult Scler J 2012;18:83542.
Fassas A, Kimiskidis VK, Sakellari I, et al. Long-term results of stem cell
transplantation for MS: a single-center experience. Neurology 2011;76:106670.
Hintzen RQ. Stem cell transplantation in multiple sclerosis: multiple choices and
multiple challenges. Mult Scler 2002;8:15560.
Muraro P, Douek D, Packer A, et al. Thymic output generates a new and diverse
TCR repertoire after autologous stem cell transplantation in multiple sclerosis
patients. J Exp Med 2005;201:80516.
Darlington PJ, Touil T, Doucet JS, et al. Diminished Th17 (not Th1) responses
underlie multiple sclerosis disease abrogation after hematopoietic stem cell
transplantation. Ann Neurol 2013;73:34154.
Burman J, Fransson M, Totterman TH, et al. T-cell responses after haematopoietic
stem cell transplantation for aggressive relapsing-remitting multiple sclerosis.
Immunology 2013;140:21119.
Saccardi R, Kozak T, Bocelli-Tyndall C, et al. Autologous stem cell transplantation
for progressive multiple sclerosis: update of the European Group for Blood and
Marrow Transplantation autoimmune diseases working party database. Mult Scler
2006;12:81423.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded
disability status scale (EDSS). Neurology 1983;33:144452.
Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Autologous hematopoietic stem cell
transplantation with reduced-intensity conditioning in multiple sclerosis.
Exp Hematol 2012;40:8928.
The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/
MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: nal
outcome of the randomized controlled trial. Neurology 1995;45:127785.
Fassas A, Nash R. Stem cell transplantation for autoimmune disorders. Multiple
sclerosis. Best Pract Res Clin Haematol 2004;17:24762.
Hankey GJ, Spiesser J, Hakimi Z, et al. Rate, degree, and predictors of recovery from
disability following ischemic stroke. Neurology 2007;68:15837.
Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics
2013;10:2933.

Burman J, et al. J Neurol Neurosurg Psychiatry 2014;0:16. doi:10.1136/jnnp-2013-307207

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Autologous haematopoietic stem cell

transplantation for aggressive multiple
sclerosis: the Swedish experience
Joachim Burman, Ellen Iacobaeus, Anders Svenningsson, et al.
J Neurol Neurosurg Psychiatry published online February 19, 2014

doi: 10.1136/jnnp-2013-307207

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